WO2017002078A1 - Inhibitors of indoleamine 2,3-dioxygenase - Google Patents

Inhibitors of indoleamine 2,3-dioxygenase Download PDF

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Publication number
WO2017002078A1
WO2017002078A1 PCT/IB2016/053947 IB2016053947W WO2017002078A1 WO 2017002078 A1 WO2017002078 A1 WO 2017002078A1 IB 2016053947 W IB2016053947 W IB 2016053947W WO 2017002078 A1 WO2017002078 A1 WO 2017002078A1
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WIPO (PCT)
Prior art keywords
mmol
compound
oxadiazol
bromo
compounds
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PCT/IB2016/053947
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English (en)
French (fr)
Inventor
Wieslaw Mieczyslaw Kazmierski
Martha De La Rosa
Vincent SAMANO
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Glaxosmithkline Intellectual Property Development Limited
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Application filed by Glaxosmithkline Intellectual Property Development Limited filed Critical Glaxosmithkline Intellectual Property Development Limited
Priority to CN201680039221.7A priority Critical patent/CN107709338A/zh
Priority to RU2018101431A priority patent/RU2018101431A/ru
Priority to ES16735943T priority patent/ES2752455T3/es
Priority to JP2017568056A priority patent/JP6654208B2/ja
Priority to EP16735943.9A priority patent/EP3317287B1/en
Priority to BR112017028456A priority patent/BR112017028456A2/pt
Priority to KR1020187003254A priority patent/KR20180022988A/ko
Priority to CA2990335A priority patent/CA2990335A1/en
Priority to AU2016285483A priority patent/AU2016285483B2/en
Priority to US15/578,861 priority patent/US10239894B2/en
Publication of WO2017002078A1 publication Critical patent/WO2017002078A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • HIV-1 Human immunodeficiency virus type 1
  • AIDS acquired immune deficiency disease
  • AIDS acquired immune deficiency disease
  • U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life.
  • additional therapies are still required due to a number of issues including but not limited to undesirable drug- drug interactions; drug-food interactions; non-adherence to therapy; drug resistance due to mutation of the enzyme target; and inflammation related to the immunologic damage caused by the HIV infection.
  • HAART highly active antiretroviral therapy
  • HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants.
  • drug resistance can still occur and the survival and quality of life are not normalized as compared to uninfected persons.
  • non-AIDS morbidities and mortalities such as cardiovascular disease, frailty, and neurocognitive impairment, are increased in HAART-suppressed, HIV-infected subjects. This increased incidence of non-AIDS morbidity/mortality occurs in the context of, and is potentially caused by, elevated systemic inflammation related to the immunologic damage caused by HIV infection.
  • IDO is a monomeric 45 kDa extrahepatic heme-containing dioxygenase which catalyzes the oxidative pyrrole ring cleavage reaction of l-Trp to /V-formylkynurenine utilizing molecular oxygen or reactive oxygen species via three proposed reaction mechanisms.
  • IDO is an enzyme that is the rate limiting step in the kynurenine pathway of tryptophan catabolism.
  • IDO catalyzes the dioxidation of the indole ring of tryptophan (Trp), producing N-formyl-lynurenine (NFK), which is then metabolized by other enzymes into several downstream metabolites such as kynurenine (Kyn) and 3-hydroxy- anthranilate (HAA).
  • Trp tryptophan
  • NFK N-formyl-lynurenine
  • NFK N-formyl-lynurenine
  • HAA 3-hydroxy- anthranilate
  • immunomodulatory activity typically exemplified by decreased T cell activation and proliferation, enrichment of regulatory CD4+ T cells, and depletion of IL-17-producing CD4+ T cells. IDO activity therefore has a general immunosuppressive impact.
  • IDO is expressed in response to inflammation and is considered an important counter balance to prevent collateral tissue damaged during prolonged inflammation. IDO expression and activity are elevated during chronic viral infections such as HIV and HCV, chronic bacterial infections, as well as acute conditions such as sepsis.
  • the IDO-mediated shift of Thl7 to Treg differentiation of helper T cells likely plays a role in the intestinal immune dysfunction during HIV infection, likely related to the observed elevated systemic inflammation and increased incidence of non-AIDS morbilidty/mortality.
  • IDO activity likely also plays a role in the persistence of pathogens and cancer, and inhibition of IDO may improve clearance mechanism, potentially leading to cure of these chronic diseases.
  • IDO may also play a role in neurological or neuropsychiatric diseases or disorders such as depression by modulating serotonin synthesis or production of excitatory neurotoxins such as kynurenine.
  • pharmacologic inhibition of IDO has application in a broad range of applications from neurology, oncology, and infectious diseases.
  • the present invention provides compounds which are modulators of IDO having Formula
  • X is CH 2 or C(0)
  • R 2 is -H or -CH 3 ;
  • R 3 is selected from the group consisting of:
  • the present invention further provides compositions comprising a compound of the invention, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the compounds of the invention have Formula (II):
  • the compounds of the invention have Formula (III):
  • the compounds of the invention have Formula (IV):
  • the compounds of the invention have Formula (V):
  • the compounds of the invention have Formula (VI):
  • the compounds of the invention have Formula (VII):
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or ACN are preferred.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present invention also includes isomers, or mixed isomers, which by definition are the molecules of identical atomic compositions, but with different bonding arrangements of atoms or orientations of their atoms in space i.e., isomers are two or more different substances with the same molecular formula.
  • Cis and trans geometic isomers of the compound of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Isomerism in the field of clinical pharmacology and pharmacotherapeutics, can differ in their pharmacokinetic and pharmacodynamic which may provide introducing safer and more effective drug alternatives of newer as well as existing drugs.
  • X is CH 2 or C(0)
  • R 2 is -H or -CH 3 ;
  • R 3 is selected from the group consisting of
  • the present invention further provides compositions comprising a compound of the invention, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating activity of indoleamine 2,3- dioxygenase by contacting the indoleamine 2,3-dioxygenase with a compound of the invention, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods for the prevention and/or treatment of HIV; including the prevention of the progression of AIDS and general immunosuppression in a patient by administering to the patient an effective amount of a compound of the invention, or
  • the present invention further provides methods of treating cancer, viral infection, bacterial infection, sepsis, macular degeneration, wounds, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, an autoimmune disease, or the like, in a patient comprising administering to the patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof.
  • the present invention further provides use of the compounds herein for the production of a medicament for use in therapy.
  • Such compounds of the present invention can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, ( )- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (S)-isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • a compound of Formulas l-VII wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment immunosuppression in a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formulas l-VII.
  • the pharmaceutical formulation containing a compound of Formulas I- VII or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the present invention is directed to compounds, compositions and pharmaceutical compositions that have utility as novel treatments for immunosuppresion. While not wanting to be bound by any particular theory, it is thought that the present compounds are able to inhibit the enzyme that catalyzes the oxidative pyrrole ring cleavage reaction of l-Trp to /V-formylkynurenine utilizing molecular oxygen or reactive oxygen species.
  • a method for the prevention and/or treatment of HIV including the prevention of the progression of AIDS and general immunosuppression.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other therapeutic agents.
  • the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by
  • administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of Formula l-VII or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors include an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • nevirapine delavirdine, efavirenz, loviride
  • immunocal immunocal
  • oltipraz immunocal
  • capravirine capravirine
  • lersivirine GSK2248761
  • TMC-278 TMC-125
  • etravirine and similar agents
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T-1249, P O-542, PROMO, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix and similar agents;
  • Integrase inhibitors such as raltegravir, elvitegravir, GSK1349572, GSK1265744 and similar agents;
  • Maturation inhibitors such as PA-344 and PA-457, and similar agents.
  • CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
  • combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the present invention may be used in combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV.
  • agents useful as pharmacological enhancers include, but are not limited to, ritonavir, GS-9350, and SPI-452.
  • Ritonavir is 10-hydroxy-2-methyl-5-(l-methyethyl)-l-l[2-(l-methylethyl)-4-thiazolyl]-3,6- dioxo-8,ll-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S- (5S*,8R*,10R*,11R*)] and is available from Abbott Laboratories of Abbott park, Illinois, as Norvir.
  • Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
  • Ritonavir also inhibits P450 mediated drug metabolism as well as the P-gycoprotein (Pgp) cell transport system, thereby resulting in increased concentrations of active compound within the organism.
  • Pgp P-gycoprotein
  • GS-9350 is a compound being developed by Gilead Sciences of Foster City California as a pharmacological enhancer.
  • SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer.
  • a compound of Formulas l-VII is used in combination with ritonavir.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a compound of Formulas l-VII is used in combination with GS-9350.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • a compound of Formulas l-VII is used in combination with SPI-452.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and SPI-452 is formulated as an oral composition.
  • the compound of Formulas l-VII is formulated as a long acting parenteral injection and SPI-452 is formulated as an injectable composition.
  • AIBN azobisisobutyronitrile
  • CDI ⁇ , -carbonyldiimidazole
  • the compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • N'-hydroxy-4-((2-methoxyethyl)amino)-l,2,5-oxadiazole-3- carboximidamide (1.87 kg, 9.3 mol) was dissolved in 6N hydrochloric acid aqueous solution (5.12 L). Sodium chloride (1.63 kg, 27.9 mol) was added followed by water (10.2 L) and EtOAc (10.2 L). At 3-5 °C a previously prepared aqueous solution (4.3 L) of sodium nitrite (615 g, 8.8 mol) was added slowly over 1 hr. The reaction was stirred at 3-8 °C for 2 hrs and then room temperature overnight. The reaction mixture was extracted with EtOAc (10L x 3).
  • N-Hydroxy-4-((2-methoxyethyl)amino)-l,2,5-oxadiazole-3-carbimidoyl chloride (1.5 kg, 6.8 mol) was mixed with water (10 L). The mixture was heated to 60 °C. 3-Bromo-4-fluoroaniline (1.44 kg, 7.46 mol) was added and stirred for 10 min. A warm sodium bicarbonate (0.86 kg, 10 mol) solution (10 L water) was added over 15 min. The reaction mixture was stirred at 60°C for 20 min. The reaction mixture was cooled to room temperature and extracted with EtOAc (10 L*2).
  • Chlorotrimethylsilane (3.53 L, 27.8 mol) was added as a solution in methanol (3.5 L) dropwise at a rate so that the temperature did not exceed 35 °C, and the reaction was stirred for 3.5 h at ambient temperature. The reaction was neutralized with 33 wt% solution of sodium thiosulfate
  • the mixture was purified by reverse phase C18 HPLC (10-90% ACN/water, 0.05% TFA) to provide N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'- hydroxycarbamimidoyl)-l,2,5-oxadiazol-3-yl)amino)ethyl)-l-hydroxy-lH-benzo[c] [l,2] carboxamide (16.1 mg, 0.029 mmol, 53.3 % yield) as an off-white solid.
  • the reaction was treated with additional HCI, 4M in dioxanes (6.03 m L, 24.1 mmol) and stirred at room temperature for 4 hr then refrigerated for 48 hours.
  • the reaction was returned to room temperature and treated with additional HCI, 4M in dioxanes (4 mL) and stirred for an additional 8 hours.
  • reaction mixture was purified using reverse phase chromatography (ACN/water 10-90%, 0.05% TFA, 20 min) to provide 2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-l,2,5-oxadiazol-3- yl)amino)-N-((l-hydroxy-l,3-dihydrobenzo[c] [l,2]oxaborol-4-yl)methyl)-N-methylacetamide, 0.5 trifluoroacetic acid salt (44 mg, 0.074 mmol, 59.1 % yield) as a white solid.
  • the reaction mixture was stirred at room temperature for 45 minutes. The reaction was then treated by the slow dropwise addition of IN NaOH (5 mL) and then stirred for 40 minutes. The reaction was then treated with IN NaOH (2 mL) and stirred for 1.5 hours. The reaction was kept in the refrigerator overnight and taken and treated with additional IN NaOH (5 m L) and stirred for 3.5 hours.
  • reaction mixture was purified using reverse phase chromatography (ACN/water 10- 90%, 0.05% TFA, 15 min) to provide N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'- hydroxycarbamimidoyl)-l,2,5-oxadiazol-3-yl)amino)ethyl)-l-hydroxy-l,3- dihydrobenzo[c] [l,2]oxaborole-7-carboxamide, 0.2 trifluoroacetic acid salt (380 mg, 0.680 mmol, 41.0 % yield) as a white solid.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formulas l-VII or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases. Accordingly, the word “or” in the context of "a compound or a pharmaceutically acceptable salt thereof” is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.
  • pharmaceutically acceptable salts of compounds according to Formulas l-VII may be prepared.
  • pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Illustrative pharmaceutically acceptable acid salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenes
  • Illustrative pharmaceutically acceptable inorganic base salts of the compounds of the present invention include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences.
  • Exemplary base salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Other exemplary base salts include the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Still other exemplary base salts include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na 2 C0 3 , K 2 C0 3 , NaH, and potassium-t-butoxide.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine
  • salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Compounds of Formulas l-VII containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formulas l-VII contains an amidoxime or alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where in some embodiements or alternate embodiments the compounds of Formulas l-VII contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where in some embodiements or alternate embodiments the compounds of Formulas l-VII contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formulas l-VII wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formulas l-VII for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds of Formulas l-VII can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
  • the compounds of the present invention may be administered as prodrugs.
  • certain derivatives of compounds of Formulas l-VII which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I as 'prodrugs'.
  • Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly.
  • oral or parenteral administration is used.
  • Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like.
  • the chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington 's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • a gelatin capsule e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject.
  • composition will comprise from about 0.2 to 2% of the active agent in solution.
  • compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
  • the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the chemical entity, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used the route and form of administration, and other factors.
  • the drug can be administered more than once a day, such as once or twice a day.
  • Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01- 100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
  • the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral systemic
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another manner for administering the provided chemical entities is inhalation.
  • the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (M DI) and dry powder inhalers (DPI).
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • M DIs typically are formulation packaged with a compressed gas.
  • the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules.
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a chemical entity described herein in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art.
  • the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients.
  • the at least one chemical entity described herein is present at a level of about 1-80 wt%.
  • Graph 1 Rat Oral Pharmacokinetic (PK), Drug concentration (ng/mL) vs. Time (hours) flat PO Smg/kg
  • IDOi enzyme assay Compounds of the present invention were tested against indoleamine 2,3 dioxygenase (IDOl) in an absorbance readout assay. IDOl catalyzes tryptophan oxidation using L- or D-tryptophan and molecular oxygen as substrates to form N-formylkynurenine (NFK). NFK has an absorbance peak near 320 nm, which allows the reaction progress to be monitored
  • test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.5 ⁇ in 384-well, UV-Star, flat bottom plates (Greiner Bio-One, Kremsmunster, Austria) to generate 11-point dose response curves.
  • Low control wells (100% inhibition, 0% NFK) contained 0.5 ⁇ of DMSO in the absence of IDOl
  • high control wells (0% inhibition, 100% NFK) contained 0.5 ⁇ of DMSO in the presence of the enzyme.
  • a 2X enzyme solution with a composition of 100 mM potassium phosphate (pH 7.2), 1 mM CHAPS, 40 mM L-ascorbic acid, 2 ⁇ methylene blue, 1% v/v catalase (Sigma-Aldrich, St. Louis, MO) and 100 nM IDOl were added to all wells of the 384-well compound plates, with the exception of the low control wells.
  • the low control wells received 25 ⁇ of a similar 2X solution lacking the IDOl enzyme. Before addition of substrate to the plates, the enzyme solution and compounds were allowed to preincubate at room temperature for 30 minutes.
  • a 2X substrate solution with a composition of 100 mM potassium phosphate (pH 7.2), 1 mM CHAPS, and 4 mM D-tryptophan (Sigma-Aldrich, St. Louis, MO) were added to all wells of the 384-well compound plates.
  • the final assay composition in the plate was 100 mM potassium phosphate (pH 7.2), 1 mM CHAPS, 20 mM L-ascorbic acid, 1 ⁇ methylene blue, 0.5% v/v catalase, +/- 50 nM IDOl, and 2 mM D-tryptophan.
  • the data for dose responses were plotted as % IDOl inhibition versus compound concentration following normalization using the formula 100-(100*((U-C2)/(C1-C2))), where U was the unknown value, CI was the average of the high (100% NFK; 0% inhibition) control wells and C2 was the average of the low (0% NFK; 100% inhibition) control wells.
  • HeLa IDOi assay Compounds of the present invention were tested via high-throughput cellular assays utilizing detection of kynurenine via mass spectrometry and cytotoxicity as end- points.
  • human epithelial HeLa cells CCL-2; ATCC", Manassas, VA
  • IFN- ⁇ human interferon- ⁇
  • IDOI indoleamine 2, 3-dioxygenase
  • Compounds with IDOI inhibitory properties decreased the amount of kynurenine produced by the cells via the tryptophan catabolic pathway.
  • Cellular toxicity due to the effect of compound treatment was measured using CellTiter-Glo * reagent (CTG) (Promega Corporation, Madison, Wl), which is based on luminescent detection of ATP, an indicator of metabolically active cells.
  • CTG CellTiter-Glo * reagent
  • test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.5 ⁇ in 384-well, polystyrene, clear bottom, tissue culture treated plates with lids (Greiner Bio-One, Kremsmunster, Austria) to generate 11-point dose response curves.
  • Low control wells contained either 0.5 ⁇ of DMSO in the presence of unstimulated (-IFN- ⁇ ) HeLa cells for the mass spectrometry assay or 0.5 ⁇ of DMSO in the absence of cells for the cytotoxicity assay, and high control wells (100% kynurenine or 0% cytotoxicity) contained 0.5 ⁇ of DMSO in the presence of stimulated (+IFN-y) HeLa cells for both the mass spectrometry and cytotoxicity assays.
  • Frozen stocks of HeLa cells were washed and recovered in DMEM high glucose medium with HEPES (Thermo Fisher Scientific, Inc., Waltham, MA) supplemented with 10% v/v certified fetal bovine serum (FBS) (Thermo Fisher Scientific, Inc., Waltham, MA), and IX penicillin-streptomycin antibiotic solution (Thermo Fisher Scientific, Inc., Waltham, MA).
  • FBS v/v certified fetal bovine serum
  • IX penicillin-streptomycin antibiotic solution Thermo Fisher Scientific, Inc., Waltham, MA.
  • the cells were diluted to 100,000 cells/mL in the supplemented DMEM medium.
  • cytotoxicity assay For the cytotoxicity assay, CellTiter-Glo * was prepared according to the manufacturer's instructions, and 10 ⁇ were added to each plate well. After a twenty minute incubation at room temperature, luminescence was read on an EnVision * Multilabel Reader (PerkinElmer Inc., Waltham, MA). For the mass spectrometry assay, 10 ⁇ of supernatant from each well of the compound-treated plates were added to 40 ⁇ of acetonitrile, containing 10 ⁇ of an internal standard for normalization, in 384-well, polypropylene, V-bottom plates (Greiner Bio-One, Kremsmunster, Austria) to extract the organic analytes.
  • the data for dose responses in the mass spectrometry assay were plotted as % IDOl inhibition versus compound concentration following normalization using the formula 100-(100*((U- C2)/(C1-C2))), where U was the unknown value, CI was the average of the high (100% kynurenine; 0% inhibition) control wells and C2 was the average of the low (0% kynurenine; 100% inhibition) control wells.
  • the data for dose responses in the cytotoxicity assay were plotted as % cytotoxicity versus compound concentration following normalization using the formula 100-(100*((U-C2)/(C1- C2))), where U was the unknown value, CI was the average of the high (0% cytotoxicity) control wells and C2 was the average of the low (100% cytotoxicity) control wells.
  • the results for each test compound were recorded as plC50 values for the mass spectrometry assay and as pCC50 values for the cytoxicity assay (-C in the above equation).
  • PBMC IDOi assay Compounds of the present invention were tested via high-throughput cellular assays utilizing detection of kynurenine via mass spectrometry and cytotoxicity as end- points.
  • PBMC peripheral blood mononuclear cells
  • IFN- ⁇ human interferon- ⁇
  • LPS lipopolysaccharide from Salmonella minnesota
  • Compounds with IDOl inhibitory properties decreased the amount of kynurenine produced by the cells via the tryptophan catabolic pathway.
  • Cellular toxicity due to the effect of compound treatment was measured using CeNTiter-Glo * reagent (CTG) (Promega Corporation, Madison, Wl), which is based on luminescent detection of ATP, an indicator of metabolically active cells.
  • CCG CeNTiter-Glo * reagent
  • test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.5 ⁇ in 384-well, polystyrene, clear bottom, tissue culture treated plates with lids (Greiner Bio-One, Kremsmunster, Austria) to generate 11-point dose response curves.
  • Low control wells contained either 0.5 ⁇ of DMSO in the presence of unstimulated (-IFN-y/-LPS) PBMCs for the mass spectrometry assay or 0.5 ⁇ of DMSO in the absence of cells for the cytotoxicity assay, and high control wells (100% kynurenine or 0% cytotoxicity) contained 0.5 ⁇ of DMSO in the presence of stimulated (+IFN-y/+LPS) PBMCs for both the mass spectrometry and cytotoxicity assays.
  • Frozen stocks of PBMCs were washed and recovered in RPMI 1640 medium (Thermo Fisher Scientific, Inc., Waltham, MA) supplemented with 10% v/v heat-inactivated fetal bovine serum (FBS) (Thermo Fisher Scientific, Inc., Waltham, MA), and IX penicillin-streptomycin antibiotic solution (Thermo Fisher Scientific, Inc., Waltham, MA).
  • FBS v/v heat-inactivated fetal bovine serum
  • IX penicillin-streptomycin antibiotic solution Thermo Fisher Scientific, Inc., Waltham, MA.
  • the cells were diluted to 1,000,000 cells/mL in the supplemented RPMI 1640 medium.
  • the data for dose responses in the mass spectrometry assay were plotted as % IDOl inhibition versus compound concentration following normalization using the formula 100-(100*((U- C2)/(C1-C2))), where U was the unknown value, CI was the average of the high (100% kynurenine; 0% inhibition) control wells and C2 was the average of the low (0% kynurenine; 100% inhibition) control wells.
  • the data for dose responses in the cytotoxicity assay were plotted as % cytotoxicity versus compound concentration following normalization using the formula 100-(100*((U-C2)/(C1- C2))), where U was the unknown value, CI was the average of the high (0% cytotoxicity) control wells and C2 was the average of the low (100% cytotoxicity) control wells.
  • the results for each test compound were recorded as plC50 values for the mass spectrometry assay and as pCC50 values for the cytoxicity assay (-C in the above equation).
  • IDOi MDDC assay Compounds of the present invention were tested via a high-throughput cellular assay utilizing detection of kynurenine via mass spectrometry.
  • Human monocyte-derived dendritic cells (MDDC) (AllCeHs * , Alameda, CA) were stimulated with human interferon- ⁇ (IFN- ⁇ ) (Sigma-Aldrich Corporation, St. Louis, MO) and lipopolysaccharide from Salmonella minnesota (LPS) (Invivogen, San Diego, CA) to induce the expression of indoleamine 2, 3-dioxygenase (IDOl).
  • IFN- ⁇ human interferon- ⁇
  • LPS lipopolysaccharide from Salmonella minnesota
  • IDOl indoleamine 2, 3-dioxygenase
  • test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.5 ⁇ in 384-well, polystyrene, clear bottom, tissue culture treated plates with lids (Greiner Bio-One, Kremsmunster, Austria) to generate 11-point dose response curves.
  • Low control wells (0% kynurenine) contained 0.5 ⁇ of DMSO in the presence of unstimulated (-IFN-y/-LPS) MDDCs
  • high control wells (100% kynurenine) contained 0.5 ⁇ of DMSO in the presence of stimulated (+IFN-y/+LPS) MDDCs.
  • Frozen stocks of MDDCs were washed and recovered in RPMI 1640 medium (Thermo Fisher Scientific, Inc., Waltham, MA) supplemented with 10% v/v heat-inactivated fetal bovine serum (FBS) (Thermo Fisher Scientific, Inc., Waltham, MA), and IX penicillin-streptomycin antibiotic solution (Thermo Fisher Scientific, Inc., Waltham, MA).
  • FBS fetal bovine serum
  • IX penicillin-streptomycin antibiotic solution Thermo Fisher Scientific, Inc., Waltham, MA.
  • the cells were diluted to 1,000,000 cells/mL in the supplemented RPMI 1640 medium. 50 ⁇ of the cell suspension were added to the low control wells, on the previously prepared 384-well compound plates, resulting in 50,000 cells/well.
  • IFN- ⁇ and LPS were added to the remaining cell suspension at final concentrations of 100 ng/ml and 50 ng/ml respectively, and 50 ⁇ of the stimulated cells were added to all remaining wells on the 384- well compound plates. The plates, with lids, were then placed in a 37°C, 5% C0 2 humidified incubator for 2 days.
  • the data for dose responses in the mass spectrometry assay were plotted as % IDOl inhibition versus compound concentration following normalization using the formula 100-(100*((U- C2)/(C1-C2))), where U was the unknown value, CI was the average of the high (100% kynurenine; 0% inhibition) control wells and C2 was the average of the low (0% kynurenine; 100% inhibition) control wells.
  • DMSO/solutol/10% hydroxyl-propyl ⁇ cyclodextrin (10:10:80) dosing vehicle For all animals,food and water was provided ad libitum. Blood samples were withdrawn from a surgically-implanted venous cannula at timed intervals for 24 h after dose administration, treated with EDTA, and centrifuged to harvest plasma for LC/MS/MS analysis. Plasma concentration-time data for individual rats were analyzed by noncompartmental analysis using the PhoenixTM WinNonlin * (version 6.2.1, Pharsight Corp., St. Louis, MO) software to generate pharmacokinetic parameter estimates.
  • PhoenixTM WinNonlin * version 6.2.1, Pharsight Corp., St. Louis, MO

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